Induction of cytochrome P450 4A14 contributes to angiotensin II-induced renal fibrosis in mice
Induction of cytochrome P450 4A14 contributes to angiotensin II-induced renal fibrosis in mice
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细胞色素 P450 4A14 的诱导有助于血管紧张素 II 诱导的小鼠肾纤维化
DOI：
10.1016/j.bbadis.2017.12.028
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发表时间：
2018-03-01
影响因子：
6.2
通讯作者：
Guan, Youfei
中科院分区：
文献类型：
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作者：
Zhou, Yunfeng;Yu, Jingwei;Guan, Youfei
血管紧张素II（AngII）在高血压及其相关肾损害的发病机制中起重要作用。为了阐明AngII诱导肾损伤的分子机制，我们发现AngII输注显著诱导肾近端小管细胞（RPTC）中CYP 4A 14的表达，伴随血压和蛋白尿的显著增加。肾脏产生的主要CYP 4A代谢产物，20-HETE，也显着增加，在血管紧张素II治疗的小鼠。与野生型（WT）小鼠相比，CYP 4A 14敲除（CYP 4A 14（-/-））小鼠在AngII输注后表现出显著较低水平的血压、肾20-HETE产生、蛋白尿和肾纤维化。此外，在CYP 4A 14（-/-）小鼠中，AngII诱导的促纤维化基因和促炎基因的肾脏表达显著减弱。使用培养的RPTC进行的体外研究表明，AngII通过MAPK信号通路显著诱导CYP 4A 14表达和20-HETE产生。AngII治疗增加TGF-β和胶原蛋白表达，这被CYP 4A抑制剂TS-011减弱。此外，20-HETE治疗有效诱导CYP 4A 14表达和TGF-β和胶原蛋白水平。总的来说，这些发现表明，AngII治疗的CYP 4A 14（-/-）小鼠中肾纤维化减弱可能是由于全身血压降低和肾20-HETE产生减少。因此，CYP 4A 14可能是治疗AngII相关肾损伤的有用靶点。
Angiotensin II (AngII) plays an important role in the pathogenesis of hypertension and associated renal injuries. To elucidate the molecular mechanism by which AngII induces renal damage, we found that AngII infusion significantly induced CYP4A14 expression in renal proximal tubule cells (RPTCs) with marked increases in blood pressure and proteinuria. Renal production of the major CYP4A metabolite, 20-HETE, was also significantly increased in the AngII-treated mice. Compared to wild-type (WT) mice, CYP4A14 knockout (CYP4A14(-/-)) mice exhibited significantly lower levels of blood pressure, renal 20-HETE production, proteinuria and renal fibrosis following AngII infusion. Furthermore, AngII-induced renal expression of profibrotic genes and proinflammatory genes was significantly attenuated in CYP4A14(-/-) mice. In vitro studies using cultured RPTCs demonstrated that AngII significantly induced CYP4A14 expression and 20-HETE production via the MAPK signaling pathway. AngII treatment increased TGF-beta and collagen expression, which was attenuated by the CYP4A inhibitor, TS-011. Moreover, 20-HETE treatment potently induced CYP4A14 expression and TGF-beta and collagen levels. Collectively, these findings suggest that attenuated renal fibrosis in AngII-treated CYP4A14(-/-) mice may result from both reduced systemic blood pressure and renal 20-HETE production. Therefore, CYP4A14 may represent a useful target for the treatment of AngII-associated renal damage.